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| 3. |
- Abdelmagid, N., et al.
(author)
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The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat
- 2012
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In: Plos Pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 8:6
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Journal article (peer-reviewed)abstract
- Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3-31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.
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| 4. |
- Luhr, JJ, et al.
(author)
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Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition
- 2020
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In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 11, s. 590121-
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Journal article (peer-reviewed)abstract
- Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.
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| 6. |
- Frey, H U, et al.
(author)
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Freja and ground-based analysis of inverted-V events
- 1998
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In: JOURNAL OF GEOPHYSICAL RESEARCH-SPACE PHYSICS. - 0148-0227. ; 103:A3, s. 4303-4314
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Journal article (peer-reviewed)abstract
- During two campaigns, ground-based auroral observations were performed in coordination with Freja. The high temporal and spatial resolution of the satellite instruments as well as the real-time recording with a stereoscopic camera system from the ground enabled detailed comparison of small- and large-scale optical phenomena with particle and field data measured by the satellite. Three passes of the satellite over inverted-V auroral arcs and over precipitation regions with strong field-aligned electron spectra are investigated. Brightness modulations within auroral arcs coincide with modulations of primary electron fluxes. The dynamics of small-scale structures within arcs as well as the proper motion of arcs are analyzed and compared with electric fields measured by the satellite and with BARS radar measurements. Energy fluxes independently determined from the ground and from the satellite are used to calculate the field-aligned conductance. The results agree with predictions of the kinetic theory of the mirror force, if we allow for variations of the density and thermal energy of the electrons in the source region of the magnetosphere. Detailed comparison of electron spectra and electric and magnetic field perturbations provide evidence of different acceleration mechanisms for the electrons, electrostatic acceleration inside inverted-V's, and wave acceleration in transient regions.
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| 9. |
- Luhr, Katarina M
(author)
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Prion processing and propagation in neuronal and dendritic cell culture models
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Prion diseases are rare neurodegenerative diseases, associated with a conversion of a normal cellular protein, PrPC, into its misfolded and partial protease resistant isoform, PrPSc. These diseases affect both animals and humans and are unique since they can not only be genetic and sporadic, but also transmissible. When affecting the central nervous system (CNS), the prion diseases are lethal and characterized by accumulations of PrPSc, spongiform changes and astrogliosis. The cause of the neurodegeneration is not known, but has been shown to correlate with accumulations of misfolded PrPSc. The aim of this work is to study how the amount of PrPSc can be regulated in neurons and cells of the immune system to affect processing and spread of this protein. For this purpose we used cell-culture models of neuronal cells and antigen presenting cells. The immortalized hypothalamic GT1-1 cell line and primary cultures of mouse dorsal root ganglia (DRG) were used as a source of neuronal cells. Antigen presenting cells were represented by primary cultures of mouse bone marrow-derived CD11c+ dendritic cells. The results show that PrPSc can be degraded by cellular cysteine proteases in scrapie-infected GT1-1 cells (ScGT1-1). After incubation of ScGT1-1 with cysteine protease inhibitors, levels of PrPSc were increased as visualized by Western immunoblotting and immunofluorescence. Inhibitors of other protease families did not exert any effects on the PrPSc amount in these cells. Inhibition of both cathepsin B and cathepsin L by selective protease inhibitors and by siRNA increased the amount of PrPSc in ScGT1-1 cells. After blocking formation of PrPSc using pentosan polysulfate, the increase in PrPSc induced by the inhibitors was still evident showing that the inhibitors were acting on degradation, not formation of misfolded protein. Since IFN-gamma can affect the activity of cathepsins, the ScGT1-1 cells were exposed to this proinflammatory cytokine. IFN-gamma exposure lead to an increase in the activity of cathepsin L in the ScGT1-1 cells, visualized with the Magic red cathepsin L activity-assay. The increase in cathepsin L activity was followed by a decrease in the levels of PrPSc in the cells. Inhibitors of cathepsin B and cathepsin L could block this decrease of PrPSc in IFN-gamma treated cells. Combined treatment with IFN-gamma and pentosan polysulfate removed all trace of PrPSc in the cells, unlike after treatment with pentosan polysulfate alone, where still some remains of PrPSc could be seen. Bone marrow-derived dendritic cells (DCs) may be involved in the spread of prions in vivo. Cultured DCs did not express detectable levels of PrPC, and could therefore not form PrPSc. These cultured DCs were instead used as a model to study PrPSc degradation. After exposure of the DCs to PrPSc, the DCs were shown to degrade PrPSc. Inhibitors of cysteine proteases could block this degradation. The clearance of PrPSc occurred at acidic pH, implicating a role for the lysosomal proteases also in PrPSc degradation in this cell type. Finally, primary cultures of dorsal root ganglia, containing neurons, Schwann cells or satellite cells (glial cells) and macrophage-like cells were exposed to homogenates from scrapie-infected GT1-1 cells. PrPSc could be visualized by immunofluorescence in the glial cells and the macrophage-like cells. However, after prolonged exposure, the glial cells were cleared of PrPSc, but a few PrPSc labeled neurons were found in the cultures. After exposure to the homogenate of ScGT1-1 cells together with an inhibitor of cysteine and serine proteases, PrPSc remained in the glial cells and macrophage-like cells for extended periods of time. DRG neurons could also be cultivated together with DCs. Thus, primary cultures of dorsal root ganglion cells may serve as a model for studies on PrPSc processing and spread.
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| 13. |
- Luhr, O R, et al.
(author)
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The impact of respiratory variables on mortality in non-ARDS and ARDS patients requiring mechanical ventilation.
- 2000
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In: Intensive care medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 26:5, s. 508-17
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Journal article (peer-reviewed)abstract
- Primarily, to determine if respiratory variables, assessed on a daily basis on days 1-6 after ICU admission, were associated with mortality in non-ARDS and ARDS patients with respiratory failure requiring mechanical ventilation. Secondarily, to determine non-respiratory factors associated with mortality in ARDS and non-ARDS patients.Prospective multicentre clinical study.Seventy-eight intensive care units in Sweden and Iceland.Five hundred twenty non-ARDS and 95 ARDS patients.Potentially prognostic factors present at inclusion were tested against 90-day mortality using a Cox regression model. Respiratory variables (PaO2/FIO2, PEEP, mean airway pressure (MAP) and base excess (BE)) were tested against mortality using the model. Primary aim: in non-ARDS a low PaO2/FIO2 on day 1, RR (risk ratio) = 1.17, CI (95% confidence interval) (1.00; 1.36), day 4, 1.24 (1.02; 1.50), day 5, 1.25 (1.02; 1.53) and a low MAP at baseline, 1.18 (1.00; 1.39), day 2, 1.24 (1.02; 1.52), day 3, 1.33 (1.06; 1.67), day 6, 2.38 (1.11; 5.73) were significantly associated with 90-day death. Secondary aim: in non-ARDS a low age, RR = 0.77 (0.67; 0.89), female gender, 0.85 (0.74; 0.98), and low APS (acute physiologic score), 0.85 (0.73; 0.99), were associated with survival; chronic disease, 1.31 (1.12; 1.52), and non-pulmonary origin to the respiratory failure, 1.27 (1.10; 1.47), with death. In ARDS low age, RR = 0.65 CI (0.46; 0.91), and low APS, 0.65 (0.46; 0.90), were associated with survival.No independent significant association was seen between 90-day mortality and degree of hypoxaemia, PEEP, MAP or BE for the first full week of ICU care in either ARDS or non-ARDS. In a sub-group of non-ARDS a lower PaO2/FIO2 and MAP tended to influence mortality where a significant association was seen for 3 of 7 study days. Age, gender, APS, presence of a chronic disease and a pulmonary/non-pulmonary reason for the respiratory failure were associated with mortality in non-ARDS, while only age and APS showed a similar association in ARDS.
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| 14. |
- Norqvist, P, et al.
(author)
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Ion cyclotron heating in the dayside magnetosphere
- 1996
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In: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 101:A6, s. 13179-13193
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Journal article (peer-reviewed)abstract
- Observations of waves and particles obtained by the Freja satellite at altitudes around 1700 km in the dayside high-latitude magnetosphere are used to study ion energization. We find that ions, including O+, during several events of intense ion energization can be heated perpendicularly to the geomagnetic field to mean energies df up to about 20 eV via the process of cyclotron resonance by broadband waves around the ion gyrofrequencies. There is a good correlation between such broadband waves and the ion energization. The waves show no spectral features at the O+ gyrofrequency. The observed wave amplitudes are used as an input to a Monte Carlo simulation to obtain the observed ion energies. The waves around the ion gyrofrequencies may be generated either by field-aligned electrons or by nonlinear processes transferring energy from waves with lower frequencies. Not only the mean energy but also the shape of the particle distribution agrees with the cyclotron resonance heating mechanism. Other mechanisms, such as heating by lower hybrid waves or by a slowly varying electric field, are investigated but are found to be less important than cyclotron heating in this region of space.
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| 15. |
- Norqvist, P, et al.
(author)
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Ion cyclotron heating in the dayside magnetosphere
- 1996
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In: JOURNAL OF GEOPHYSICAL RESEARCH-SPACE PHYSICS. - : AMER GEOPHYSICAL UNION. - 0148-0227. ; 101:A6, s. 13179-13193
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Journal article (other academic/artistic)abstract
- Observations of waves and particles obtained by the Freja satellite at altitudes around 1700 km in the dayside high-latitude magnetosphere are used to study ion energization. We find that ions, including O+, during several events of intense ion energizati
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| 16. |
- Rouvinski, A, et al.
(author)
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Live imaging of prions reveals nascent PrPSc in cell-surface, raft-associated amyloid strings and webs
- 2014
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In: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 204:3, s. 423-441
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Journal article (peer-reviewed)abstract
- Mammalian prions refold host glycosylphosphatidylinositol-anchored PrPC into β-sheet–rich PrPSc. PrPSc is rapidly truncated into a C-terminal PrP27-30 core that is stable for days in endolysosomes. The nature of cell-associated prions, their attachment to membranes and rafts, and their subcellular locations are poorly understood; live prion visualization has not previously been achieved. A key obstacle has been the inaccessibility of PrP27-30 epitopes. We overcame this hurdle by focusing on nascent full-length PrPSc rather than on its truncated PrP27-30 product. We show that N-terminal PrPSc epitopes are exposed in their physiological context and visualize, for the first time, PrPSc in living cells. PrPSc resides for hours in unexpected cell-surface, slow moving strings and webs, sheltered from endocytosis. Prion strings observed by light and scanning electron microscopy were thin, micrometer-long structures. They were firmly cell associated, resisted phosphatidylinositol-specific phospholipase C, aligned with raft markers, fluoresced with thioflavin, and were rapidly abolished by anti-prion glycans. Prion strings and webs are the first demonstration of membrane-anchored PrPSc amyloids.
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| 17. |
- Zhang, C., et al.
(author)
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Near Earth Vortices Driving of Field Aligned Currents Based on Magnetosphere Multiscale and Swarm Observations
- 2019
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In: Chinese Journal of Space Science. - : National Space Science Center, Chinese Academy of Sciences. - 0254-6124. ; 39:1, s. 9-17
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Journal article (peer-reviewed)abstract
- A long-standing mystery in the study of Field-Aligned Currents (FACs) has been that: how the currents are generated and why they appear to be much stronger at high altitudes than in the ionosphere. Here we present two events of magnetotail FACs observed by the Magnetospheric Multiscale Spacecraft (MMS) on 1st July and 14th July 2016, to show how the Substorm Current Wedges (SCW) were formed. The results show that particles were transferred heading towards the Earth during the expansion phase of substorms. The azimuthal flow formed clockwise (counter-clockwise) vortex-like motion, and then generated downward (upward) FACs on the tailward/poleward side of the distorted field with opposite vorticity on their Earthward/equatorward side. We also analyzed the Region 1 FACs observed by the Earth Explorer Swarm spacecraft on 1st July 2016 and found that they were associated with FACs observed by MMS, although differing by a factor of 10. This difference suggests that either there was the closure of the currents at altitudes above 500 km or the currents were not strictly parallel to B and closed at longitudes away from where they were generated.
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